Substituted 2,4-diamino-5-benzyl pyrimidines

ABSTRACT

Compounds of the formula   WHERE R is benzyl, alkoxy substituted benzyl, allyl, or halogenalkyl. The compounds are useful as antibacterial agents.

United States Patent Roth et al.

[451 Sept. 19,1972

[54] SUBSTITUTED 2,4-DIAMINO-5- BENZYL PYRIMIDINES [72] Inventors: Barbara Roth, Scarsdale; Justina Strelitz, Dobbs Ferry, both of NY.

[73] Assignee: Burroughs Wellcome 8: Co. (U.S.A.)

Inc., Tuckahoe, NY.

abandoned.

[52] US. Cl. ..260/256.4 N, 424/251 [51] Int. Cl. ..C07d-51/42 [58] Field of Search ..260/256.4 N

[56] References Cited UNITED STATES PATENTS 3,485,840 12/1969 Hoffer ..260/251 Primary Examiner-Alex Mazel Assistant Examiner-R. V. Rush Attorney-Dike, Bronstein, Roberts & Cushman [57] ABSTRACT Compounds of the formula OCHa NH2 ,ZTCHVQOR Inn-L 011 \N 3 where R is benzyl, alkoxy substituted benzyl, allyl, or halogenalkyl. The compounds are useful as antibacterial agents.

6 Claims, No Drawings SUBSTITUTED 2,4-DIAMINO--BENZYL PYRIMIDINES OCH:

wherein R is an alkyl group which my also bear a halogen substitution. The known 2,4-diamino-5-[3 ,4,5-trimethoxybenzyl]pyrimidine (T rimethoprim) (in Formula I R =CH is an antibacterial agent of proved value. (See US. Pat. No. 2,909,522, issued Oct. 20, 1959). The variants wherein R is a higher alkyl group are also active and have certain advantages of distribution and penetration.

Additionally this invention provides novel compounds of formula I, wherein R is a halogenoalkyl group such as chloroalkyl, bromoalkyl and iodoalkyl groups or an alkenyl or aralkyl. It has been found that these compounds provide significant advantages in distribution and penetration with respect to treating selective bacterial infections in mammals. In particular these new and novel compounds are particularly.effective against Staphylococcus aureus, Aerobacter aerogenes and Eschericia coli.

The new and novel compounds of Formula 'I where R is a halogenoalkyl group. or an unsaturated group such as an ally] group may preferably be given orally as tablets, capsules, etc., as bases or salts or may be injected in solution. The preferred dosages for these compounds are 5 to mg/kg, of mammal body weight when given 2 to 3 times per day.

if a salt is used, the anion thereof must be devoid of inherent toxicity. Salts of the following acids are preferred: hydrochloric, phosphoric, succinic, lactic, acetic, pyruvic, oxaloacetic, fumaric, citric and isethionic.

I In addition, the compounds of Formula I are particularly useful as antibacterials in combination with sulfa compounds. For example, the combination of a sulfonamide and the compound of Formula I may be given orally as tablets, capsules, etc. For oral administration, 400-600 mg. of sulfonamide may be combined with 100-200 mg. of the compounds of Formula I and be given once to twice per day. These drugs act synergistically to provide an overall improved effect against the bacterial infections being treated.

ln the method of the present invention the compounds of Formula I are prepared by the reaction of the corresponding 4'-hydroxy compound of Formula II with an alkyl halide in the presence of a slight excess of alkali (base). The alkyl halides may be selected from .the class comprising alkyl chlorides, alkyl bromides and alkyl iodides.

Although ll has four nitrogen atoms that are capable of reacting with alkyl halides, it has been found that if the substance is kept in the anionic condition by employing a slight excess of alkali, the oxygen is alkylated preferentially and ll is converted to l without serious loss.

The above alkylation is accomplished conveniently in an alcoholic or aqueous alcoholic solution such as in a lower alcohol. The reaction can be run at room temperature or if warmed, can be completed more rapidly. The bases which may be used are alkali hydroxides and alkoxides such as potassium hydroxide, sodium hydroxide, sodium methoxide, potassium ethoxide and other equivalents thereof.

All temperatures in this application are in degrees centigrade.

EXAMPLE 1 2,6-Dimethoxyphenol (92 g.) was slowly added to a mixture of 2N-hydrochloric acid (315 ml.), 25 percent aqueous dimethylamine ml.) and 37 percent aqueous formaldehyde solution (81 g.). An exothermic reaction occurred and the mixture turned purple. Additional 25 percent aqueous dimethylamine (50 ml.) was added and the solution was permitted to stand overnight. The product was isolated by evaporation of the solvent. The'resultant tan solid was washed well with ether, followed by recrystallization from ethanol. This produced 2,6-dimethoxy-4-(N,N- dimethylaminomethyl)phenol hydrochloride as white crystals melting at 224224.2 (dec.

A mixture of 2,4-diaminopyrimidine (3.3g), 2,6- dimethoxy-4-( N,N-dimethylaminomethyl )phenol hydrochloride (7.43 g.), sodium methoxide (1.62 g.) and glycol (40 ml.) was heated under nitrogen in an oil bath at 150 for 4 hours, during which time dimethylamine was evolved. The solvent was removed and the residual material was then recrystallized twice from dimethylformamide, which yielded 2,4-diamino- 5-( 3 ,5 '-dimethoxy-4'-hydroxybenzyl )pyrimidine as white crystals decomposing at 265-270 C.

Methyl iodide (1.42 g.) was added to a solution of 2,4-diamino-5-( 3 ,5 '-dimethoxy-4'-hydroxybenzyl)pyrimidine (2.76 g.) in 40 percent aqueous methanol (35 ml.) plus a 3.2 N-methanolic solution of potassium hydroxide (4.5 ml.). The mixture was allowed to stand in a stoppered flask at room temperature for 72 hours, after which the solvent was removed and the residue extracted with water to remove impurities. Recrystallization from ethanol yielded crystals of 2,4-diamino-5-( 3 4',5 '-trimethoxybenzyl)pyrimidine, melting at l97-199 C. and identical in all respects with the product prepared by other synthetic routes (B. Roth, E. A. Falco, G. H. I-Iitchings and S. R. M. Bush-. by, J. Med. Pharm. Chem., 5, 1103, (1962)).

EXAMPLE 2 A mixture of 2.76 grams (.01 mole) of 2,4-diamino- 1.21 grams (0.01 mole) of allyl bromide and 0.6 grams (0.0107 mole) of potassium hydroxide was dissolved in EXAMPLE 3 2,4-Diamino--[3',5-dimethoxy-4-hydroxybenzyl] pyrimidine was treated with benzyl bromide in the manner described in Example 2, to produce 2,4- diamino-5-[3,5'-dimethoxy-4-benzyloxybenzyl] pyrimidine, which melted at l62l64 C. recrystallization from dilute ethanol.

EXAMPLE 4 The reaction of 2,4-diamino-5-[3,5'-dimethoxy-4- hydroxybenzyl] pyrimidine with 1-bromo-2- chloroethane was carried out in essentially the same manner as described in Example 3. There was thus produced 2,4-diamino-5-[ 3 ,5 '-dimethoxy-4'-(,8- chloroethoxy) benzyl] pyrimidine. When recrystallized from dilute ethanol, this melted at 177-l78 C.

EXAMPLE 5 after EXAMPLE 6 In a reaction similar to that described in Example 2 octyl bromide was employed as the alkylating agent,

and there was produced 2,4-diamino-5-[3',5'- dimethoxy-4-octyloxybenzyl] pyrimidine. This substance melted at 163 C. after recrystallization from ethanol.

EXAMPLE 7 A mixture of 2.76 grams of 2,4-diamino-5-[3,5'- dimethoxy-4'-hydroxybenzyl] pyrimidine, 1.73 grams of l-bromo-B-chloropropane and 0.6 grams of potassium hydroxide was heated under reflux with 40 m1. of methanol and 10 ml. of water for a 2 hour period. The mixture was filtered from a trace of insoluble material, and the solvent removed. The residue was washed with cold water, and recrystallized from dilute ethanol, giving pure 2,4-diamin0-5-[3',5'-dimethoxy-4-('ychloropropyloxy)benzyl] pyrimidine, melting at l79l 80 C.

EXAMPLE 8 The alkylation of 2,4-diamino-5-[3,5-dimethoxy-4 '-hydroxybenzyl] pyrimidine with 3,4,5-trimethoxybenzyl chloride was carried out in a manner similar to that described in Example 2, and there was thus produced 2,4-diamino-5-[3 ,5 -dimethoxy-4'-(3 ",4 ,5"-trimethoxybenzyloxy) benzyl] pyrimidine. This melted at 164-165 C. after recrystallization from ethanol.

What is claimed is:

1. The compound selected from the class consisting of 2,4-diamino-5-[ 3 ,5 -dimethoxy-4-(B-chloroethoxy)benzyl]pyrimidine, 2,4-diamino-5-[3 ,5 '-dimethoxy- 4'-(y-chloropropoxy)benzyl]pyrimidine, 2, 4-diamino- 5-(3,5-dimethoxy-4'-allyloxybenzyl)pyrimidine, 2, 4- diamin0-5-[3,5,-dimethoxy-4-(3",4",5-trimethoxybenzyloxy)benzyl]pyrimidine and 2,4-diamin0-5-(3 ,5 '-dimethoxy-4-benzyloxybenzyl)pyrimidine.

2. 2,4-Diamino-5-[3',5-dimethoxy-4-(B- chloroethoxy)benzyl] pyrimidine.

2,4-Diamino-5-[3',5-dimethoxy-4-(-ychloropropoxy)benzyl] pyrimidine.

2,4-diamino-5-( 3 ,5 -dimethoxy-4 '-allyloxybenzyl)pyrimidine.

5. 2,4-diamino-5-[3,5-dimethoxy-4-(3",4",5"- trimethoxybenzyloxy)benzyl]pyrimidine.

6. 2 ,4-diamino-5 -(3 ,5 -dimethoxy-4-benzyloxybenzyl)pyrimidine. 

2. 2,4-Diamino-5-(3'',5''-dimethoxy-4''-( Beta -chloroethoxy)benzyl) pyrimidine.
 3. 2,4-Diamino-5-(3'',5''-dimethoxy-4''-( gamma -chloropropoxy)benzyl) pyrimidine.
 4. 2,4-diamino-5-(3'',5''-dimethoxy-4''-allyloxybenzyl)pyrimidine.
 5. 2,4-diamino-5-(3'',5''-dimethoxy-4''-(3'''',4'''',5'''' -trimethoxybenzyloxy)benzyl)pyrimidine.
 6. 2,4-diamino-5-(3'',5''-dimethoxy-4''-benzyloxybenzyl)pyrimidine. 